A randomized, double-blind, placebo-controlled trial of aldafermin in patients with NASH and compensated cirrhosis.

BACKGROUND AND AIMS: Aldafermin, an engineered analog of the human hormone FGF19, improves liver histology in patients with noncirrhotic NASH; however, its efficacy and safety in compensated cirrhosis is unknown. No drug has yet to demonstrate benefit in the compensated NASH population. APPROACH AND RESULTS: In this multicenter, double-blind, placebo-controlled, phase 2b trial, 160 patients with compensated NASH cirrhosis were randomized to aldafermin 0.3 mg (n = 7), 1 mg (n = 42), 3 mg (n = 55), or placebo (n = 56) for 48 weeks. The 0.3 mg group was discontinued to limit exposure to suboptimal doses. The primary end point was a change in Enhanced Liver Fibrosis from baseline to week 48. The analyses were performed in the intention-to-treat population. At week 48, the least-squares mean difference in the change in Enhanced Liver Fibrosis was -0.5 (95% CI, -0.7 to -0.2; p = 0.0003) between the 3 mg group and the placebo group. 15%, 21%, and 23% of patients in the placebo, 1 mg, and 3 mg group, respectively, achieved fibrosis improvement ≥ 1 stage; and 13%, 16%, and 20% achieved fibrosis improvement ≥ 1 stage without NASH worsening. Improvement in alanine aminotransferase, aspartate aminotransferase, neoepitope-specific N-terminal pro-peptide of type III collagen, and liver stiffness favored aldefermin groups over placebo. Diarrhea was the most frequent adverse event, occurring at 26% and 40% in the 1 mg and 3 mg groups, respectively, compared to 18% in the placebo group. Overall, 0%, 2%, and 9% of patients in the placebo, 1 mg, and 3 mg group, respectively, discontinued due to treatment-related adverse events. CONCLUSIONS: Aldafermin 3 mg resulted in a significant reduction in Enhanced Liver Fibrosis in patients with compensated NASH cirrhosis.

Performance of Noninvasive Tests of Fibrosis Among Asians, Hispanic, and non-Hispanic Whites in the STELLAR Trials.

BACKGROUND & AIMS: The effect of race on routinely available noninvasive tests of fibrosis is incompletely understood. This study evaluated the performance of noninvasive tests among white and Asian patients in the STELLAR trials (NCT03053050 and NCT03053063), which evaluated selonsertib in patients with advanced (F3-F4) fibrosis due to nonalcoholic steatohepatitis (NASH). METHODS: Baseline liver biopsies were centrally read using the NASH Clinical Research Network system, and 4 noninvasive tests (Nonalcoholic fatty liver disease fibrosis score [NFS], Fibrosis-4 index [FIB-4], Enhanced Liver Fibrosis test [ELF], and liver stiffness by vibration-controlled transient elastography) were measured. The performance of these tests to discriminate advanced fibrosis was evaluated using areas under the receiver operating characteristics curves with 5-fold cross-validation repeated 100 times. RESULTS: Among 3207 patients screened with evaluable liver histology, 2281 were whites and 762 were Asians. Seventy-two percent of whites and 67% of Asians had advanced fibrosis. The areas under the receiver operating characteristics curves of the noninvasive tests for advanced fibrosis were similar in whites and Asians: 0.73 and 0.75 for NFS, 0.78 and 0.80 for FIB-4, 0.79 and 0.81 for ELF, and 0.80 and 0.83 for liver stiffness, respectively. At the published cutoffs, the tests had similar sensitivities and specificities in the 2 groups. However, the sensitivities of NFS, FIB-4, and ELF were low in both white and Asian patients younger than 40 years. CONCLUSIONS: In the global phase III STELLAR trials, the diagnostic performance of routinely available noninvasive tests for the detection of advanced fibrosis due to NASH was acceptable and similar between white and Asian patients.

Efficacy and Safety of Aldafermin, an Engineered FGF19 Analog, in a Randomized, Double-Blind, Placebo-Controlled Trial of Patients With Nonalcoholic Steatohepatitis.

BACKGROUND & AIMS: Aldafermin, an engineered analog of fibroblast growth factor 19, inhibits bile acid synthesis and regulates metabolic homeostasis. We report results from a 24-week, phase 2 study, with serial liver biopsies, of patients with nonalcoholic steatohepatitis (NASH). METHODS: We performed a double-blind study of 78 patients with NASH at 9 centers in the United States. Key inclusion criteria were biopsy-proven NASH with Nonalcoholic Fatty Liver Disease Activity Score ≥4, stage 2 or 3 fibrosis by NASH Clinical Research Network classification, and absolute liver fat content ≥8%, measured by magnetic resonance imaging-proton density fat fraction. Patients were randomly assigned (1:2) to groups given subcutaneous placebo (n = 25) or aldafermin 1 mg (n = 53) daily for 24 weeks. The primary outcome was change in absolute liver fat content from baseline at week 24. Secondary outcomes included serum markers and histologic measures of fibrosis improvement and NASH resolution. RESULTS: At week 24, the aldafermin group had a significant reduction in absolute liver fat content (reduction of 7.7%) compared with placebo (reduction of 2.7%; difference, reduction of 5.0%; 95% confidence interval, reduction of 8.0%-1.9%; P = .002). Aldafermin produced significantly greater decreases in levels of 7α-hydroxy-4-cholesten-3-one, bile acids, alanine and aspartate aminotransferases, and neoepitope-specific N-terminal pro-peptide of type III collagen (Pro-C3) than placebo. Fibrosis improvement (≥1 stage) with no worsening of NASH was achieved in 38% of patients receiving aldafermin vs 18% of patients receiving placebo (P = .10). NASH resolution with no worsening of fibrosis was observed in 24% of patients given aldafermin vs 9% of patients given placebo (P = .20). Discontinuations due to adverse events occurred in no patients in the aldafermin group and 4% of patients in the placebo group. CONCLUSIONS: In a phase 2 trial of patients with NASH, aldafermin reduced liver fat and produced a trend toward fibrosis improvement. ClinicalTrials.gov, Number: NCT02443116.

Combination Therapies Including Cilofexor and Firsocostat for Bridging Fibrosis and Cirrhosis Attributable to NASH.

BACKGROUND AND AIMS: Advanced fibrosis attributable to NASH is a leading cause of end-stage liver disease. APPROACH AND RESULTS: In this phase 2b trial, 392 patients with bridging fibrosis or compensated cirrhosis (F3-F4) were randomized to receive placebo, selonsertib 18 mg, cilofexor 30 mg, or firsocostat 20 mg, alone or in two-drug combinations, once-daily for 48 weeks. The primary endpoint was a ≥1-stage improvement in fibrosis without worsening of NASH between baseline and 48 weeks based on central pathologist review. Exploratory endpoints included changes in NAFLD Activity Score (NAS), liver histology assessed using a machine learning (ML) approach, liver biochemistry, and noninvasive markers. The majority had cirrhosis (56%) and NAS ≥5 (83%). The primary endpoint was achieved in 11% of placebo-treated patients versus cilofexor/firsocostat (21%; P = 0.17), cilofexor/selonsertib (19%; P = 0.26), firsocostat/selonsertib (15%; P = 0.62), firsocostat (12%; P = 0.94), and cilofexor (12%; P = 0.96). Changes in hepatic collagen by morphometry were not significant, but cilofexor/firsocostat led to a significant decrease in ML NASH CRN fibrosis score (P = 0.040) and a shift in biopsy area from F3-F4 to ≤F2 fibrosis patterns. Compared to placebo, significantly higher proportions of cilofexor/firsocostat patients had a ≥2-point NAS reduction; reductions in steatosis, lobular inflammation, and ballooning; and significant improvements in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, cytokeratin-18, insulin, estimated glomerular filtration rate, ELF score, and liver stiffness by transient elastography (all P ≤ 0.05). Pruritus occurred in 20%-29% of cilofexor versus 15% of placebo-treated patients. CONCLUSIONS: In patients with bridging fibrosis and cirrhosis, 48 weeks of cilofexor/firsocostat was well tolerated, led to improvements in NASH activity, and may have an antifibrotic effect. This combination offers potential for fibrosis regression with longer-term therapy in patients with advanced fibrosis attributable to NASH.

A Phase 2 Double Blinded, Randomized Controlled Trial of Saroglitazar in Patients With Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH), the clinically aggressive variant of nonalcoholic fatty liver disease, is characterized by hepatocellular injury and inflammation.1 Patients with NASH are at higher risk of progression to cirrhosis and it is therefore targeted for drug development efforts.2 Lifestyle modifications and weight loss are the only recommended modalities and no drug is yet approved for the treatment of patients with NASH. Saroglitazar is a dual PPAR α/γ agonist, which has shown promise for treatment of nonalcoholic fatty liver disease.3 Because of its combined PPAR-α/γ agonism, it has a clinically favorable impact of glucose and lipid metabolism. Saroglitazar has shown to improve liver-related histology in patients with NASH and was recently approved for treatment of NASH in India.4 The current study builds on the published literature in this proof of concept study to determine if there is a signal for histologic improvement of NASH with saroglitazar in a Western population.

Role of Noninvasive Tests in Clinical Gastroenterology Practices to Identify Patients With Nonalcoholic Steatohepatitis at High Risk of Adverse Outcomes: Expert Panel Recommendations.

Nonalcoholic fatty liver disease (NAFLD) is generally considered a silent and potentially reversible condition. The subtype of NAFLD that can be classified as nonalcoholic steatohepatitis (NASH) can progress to advanced fibrosis and cirrhosis. Because of the metabolic nature of the pathogenic mechanism underlying NAFLD and NASH, it is often accompanied by common comorbidities such as obesity, insulin resistance, and type 2 diabetes mellitus. The increase in the prevalence of these comorbidities has resulted in a parallel increase in the prevalence of NAFLD and NASH, globally, nationally, and even in children. In recent years, it has been identified that the stage of fibrosis is the most important predictor of liver outcomes; therefore, identifying patients with NAFLD and NASH with more advanced stages of fibrosis can be essential for optimal management. Several noninvasive tools for diagnosing and staging NAFLD and NASH are available, but simple and straightforward recommendations on the use of these tools are not. Recognizing these unmet needs, hepatologists who are members of the American College of Gastroenterology and the Chronic Liver Disease Foundation created a practical decision tree/algorithm to risk stratify NAFLD/NASH as a resource in gastroenterology/hepatology clinical practices. This review will provide insight into how this algorithm was developed, describe it in detail, and provide recommendations for its use in clinical practice.

Safety, Tolerability, and Biologic Activity of AXA1125 and AXA1957 in Subjects With Nonalcoholic Fatty Liver Disease.

INTRODUCTION: AXA1125 and AXA1957 are novel, orally administered endogenous metabolic modulator compositions, specifically designed to simultaneously support multiple metabolic and fibroinflammatory pathways associated with nonalcoholic fatty liver disease (NAFLD). This study assessed safety, tolerability, and biologic activity of AXA1125 and AXA1957 in NAFLD. METHODS: In this multicenter, 16-week, placebo-controlled, single-blind, randomized clinical study in subjects with NAFLD stratified by type 2 diabetes, AXA1125 24 g, AXA1957 13.5 g or 20.3 g, or placebo was administered twice daily. Key metabolism (MRI-proton density fat fraction [MRI-PDFF] and homeostasis model assessment of insulin resistance [HOMA-IR]) and fibroinflammation markers (alanine aminotransferase [ALT], corrected T1 [cT1], keratin-18 [K-18] M65, and N-terminal type III collagen propeptide [Pro-C3]) were evaluated. Safety outcomes included adverse events and standard laboratory assessments. RESULTS: Baseline characteristics of the 102 enrolled subjects, including 40 with type 2 diabetes, were consistent with presumed nonalcoholic steatohepatitis. AXA1125 showed consistently greater biologic activity than AXA1957 or placebo. Week 16 changes from baseline with AXA1125 vs placebo: MRI-PDFF -22.9% vs -5.7%, HOMA-IR -4.4 vs +0.7, ALT -21.9% vs -7.2%, K-18 M65 -13.6% vs +20.1%, cT1 -69.6 vs +18.3 ms (P < 0.05), and Pro-C3 -13.6% vs -3.6%. Week 16 changes from baseline with AXA1957 20.3 g: MRI-PDFF -8.1%, HOMA-IR +8.4, ALT -20.7%, K-18 M65 6.6%, cT1 -34.7 ms, and Pro-C3 -15.6%. A greater proportion of subjects treated with AXA1125 achieved clinically relevant thresholds: ≥30% MRI-PDFF, ≥17-IU/L ALT, and ≥80-ms cT1 reductions at week 16. Study products were safe and well tolerated with stable lipid and weight profiles. DISCUSSION: Both compositions showed multitargeted activity on relevant NAFLD pathways. AXA1125 demonstrated the greatest activity over 16 weeks, warranting continued clinical investigation in nonalcoholic steatohepatitis subjects.

Quality of Care Program Reduces Unplanned Health Care Utilization in Patients With Inflammatory Bowel Disease.

INTRODUCTION: There is significant variation in processes and outcomes of care for patients with inflammatory bowel disease (IBD), suggesting opportunities to improve quality of care. We aimed to determine whether a structured quality of care program can improve IBD outcomes, including the need for unplanned health care utilization. METHODS: We used a structured approach to improve adult IBD care in 27 community-based gastroenterology practices and academic medical centers. Patient-reported outcomes (PRO) and health care utilization were collected at clinical visits. Outcomes were monitored monthly using statistical process control charts; improvement was defined by special cause (nonrandom) variation over time. Multivariable logistic regression was applied to patient-level data. Nineteen process changes were offered to improve unplanned health care utilization. Ten outcomes were assessed, including disease activity, remission status, urgent care need, recent emergency department use, hospitalizations, computed tomography scans, health confidence, corticosteroid or opioid use, and clinic phone calls. RESULTS: We collected data prospectively from 20,382 discrete IBD visits. During the 15-month project period, improvement was noted across multiple measures, including need for urgent care, hospitalization, steroid use, and opioid utilization. Adjusted multivariable modeling showed significant improvements over time across multiple outcomes including urgent care need, health confidence, emergency department utilization, hospitalization, corticosteroid use, and opioid use. Attendance at monthly coached webinars was associated with improvement. DISCUSSION: Outcomes of IBD care were improved using a structured quality improvement program that facilitates small process changes, sharing of best practices, and ongoing feedback. Spread of these interventions may facilitate broad improvement in IBD care when applied to a large population.

Health Economic Impact of a Multicenter Quality-of-Care Initiative for Reducing Unplanned Healthcare Utilization Among Patients With Inflammatory Bowel Disease.

INTRODUCTION: A multicenter adult inflammatory bowel disease learning health system (IBD Qorus) implemented clinical care process changes for reducing unplanned emergency department visits and hospitalizations using a Breakthrough Series Collaborative approach. METHODS: Using Markov decision models, we determined the health economic impact of participating in the Collaborative from the third-party payer perspective. RESULTS: Across all 23 sites, participation in the Collaborative was associated with lower annual costs by an average of $2,528 ± $233 per patient when compared with the baseline period. DISCUSSION: Implementing clinical care process changes using a Collaborative approach was associated with overall cost savings. Future work should examine which specific interventions are most effective and whether such cost savings are sustainable.

Not Achieving Sustained Viral Eradication of Hepatitis C Virus After Treatment Leads to Worsening Patient-reported Outcomes.

BACKGROUND: The causative relationship between the clearance of infections and long-term, health-related quality-of-life (HRQL) improvements in patients with hepatitis C virus (HCV) has been generally accepted. The aim of this study was to assess long-term HRQL trends in HCV patients who did not achieve sustained virologic responses (SVRs) after treatment with direct-acting antivirals. METHODS: HCV patients who completed treatment in clinical trials and did not achieve SVRs were enrolled in a long-term registry (#NCT01457768). HRQL scores were prospectively collected using the short form-36 instrument (8 HRQL domains and 2 summary scores). RESULTS: There were 242 patients included: they had a median age of 54 years (standard deviation ± 8 years), 85% were male, and 38% had cirrhosis. Before treatment, patients' HRQL scores were similar to the general population norms (all 1-sided P > 0.05), but were followed by significant decreases by the end of treatment (-3.4 to -6.2 points; P < .05 for 5/8 HRQL domains and mental summary). By the time subjects entered the registry, all but 1 of the mean HRQL scores had returned to their pretreatment levels (P > .05). During subsequent periods in the registry, patients experienced further HRQL decrements: up to -9.2 points (P < .05 for all HRQL domains) at Week 24 and up to -8.3 points (P < .05 for 5/8 HRQL domains) at Week 48. Although these HRQL decrements were observed regardless of cirrhosis status, they were more pronounced in patients with cirrhosis (P < .05 for 3/8 HRQL domains). CONCLUSIONS: Patients who did not achieve an SVR after treatment experienced worsening HRQL scores in long-term follow-ups. Retreatment of these patients will be important not only to improve their clinical outcomes, but also their quality of life.

A randomized, placebo-controlled trial of emricasan in patients with NASH and F1-F3 fibrosis.

BACKGROUND & AIMS: Non-alcoholic steatohepatitis (NASH) is characterized by hepatocyte steatosis, ballooning, and lobular inflammation which may lead to fibrosis. Lipotoxicity activates caspases, which cause apoptosis and inflammatory cytokine (IL-1ß and IL-18) production. Emricasan is a pan-caspase inhibitor that decreases serum aminotransferases and caspase activation in patients with NASH. This study postulated that 72 weeks of emricasan treatment would improve liver fibrosis without worsening of NASH. METHODS: In this double-blind, placebo-controlled study 318 patients were randomized 1:1:1 to twice-daily treatment with emricasan (5 mg or 50 mg) or matching placebo for 72 weeks. Patients had definite NASH and NASH CRN fibrosis stage F1-F3, as determined by a central reader, on a liver biopsy obtained within 6 months of randomization. RESULTS: Emricasan treatment did not achieve the primary objective of fibrosis improvement without worsening of NASH (emricasan 5 mg: 11.2%; emricasan 50 mg: 12.3%; placebo: 19.0%; odds ratios vs. placebo 0.530 and 0.588, with p = 0.972 and 0.972, respectively) or the secondary objective of NASH resolution without worsening of fibrosis (emricasan 5 mg: 3.7%; emricasan 50 mg: 6.6%; placebo: 10.5%; odds ratios vs. placebo 0.334 and 0.613, with p = 0.070 and 0.335, respectively). In the small subset of patients with consistent normalization of serum alanine aminotransferase over 72 weeks, emricasan may have improved histologic outcomes. CONCLUSIONS: Emricasan treatment did not improve liver histology in patients with NASH fibrosis despite target engagement and may have worsened fibrosis and ballooning. Caspase inhibition lowered serum alanine aminotransferase in the short-term but may have directed cells to alternative mechanisms of cell death, resulting in more liver fibrosis and hepatocyte ballooning. CLINICAL TRIAL NUMBER: Clinical Trials.gov #NCT02686762. LAY SUMMARY: Non-alcoholic steatohepatitis (NASH) is characterized by fat accumulation in liver cells, which leads to inflammation and fibrosis. Emricasan was previously shown to inhibit some of the liver enzymes which lead to liver inflammation and fibrosis. In this study, emricasan did not improve liver inflammation or fibrosis in patients with NASH and pre-existing liver fibrosis.

Randomized placebo-controlled trial of emricasan for non-alcoholic steatohepatitis-related cirrhosis with severe portal hypertension.

BACKGROUND & AIMS: Emricasan, an oral pan-caspase inhibitor, decreased portal pressure in experimental cirrhosis and in an open-label study in patients with cirrhosis and severe portal hypertension, defined as a hepatic venous pressure gradient (HVPG) ≥12 mmHg. We aimed to confirm these results in a placebo-controlled study in patients with non-alcoholic steatohepatitis (NASH)-related cirrhosis. METHODS: We performed a multicenter double-blinded study, randomizing 263 patients with NASH-related cirrhosis and baseline HVPG ≥12 mmHg to twice daily oral emricasan 5 mg, 25 mg, 50 mg or placebo in a 1:1:1:1 ratio for up to 48 weeks. The primary endpoint was change in HVPG (ΔHVPG) at week 24. Secondary endpoints were changes in biomarkers (aminotransferases, caspases, cytokeratins) and development of liver-related outcomes. RESULTS: There were no significant differences in ΔHVPG for any emricasan dose vs. placebo (-0.21, -0.45, -0.58 mmHg, respectively) adjusted for baseline HVPG, compensation status, and non-selective beta-blocker use. Compensated patients (n = 201 [76%]) tended to have a greater decrease in HVPG (emricasan all vs. placebo, p = 0.06), the decrease being greater in those with higher baseline HVPG (p = 0.018), with a significant interaction between baseline HVPG (continuous, p = 0.024; dichotomous at 16 mmHg [median], p = 0.013) and treatment. Biomarkers decreased significantly with emricasan at week 24 but returned to baseline levels by week 48. New or worsening decompensating events (∼10% over median exposure of 337 days), progression in model for end-stage liver disease and Child-Pugh scores, and treatment-emergent adverse events were similar among treatment groups. CONCLUSIONS: Despite a reduction in biomarkers indicating target engagement, emricasan was not associated with improvement in HVPG or clinical outcomes in patients with NASH-related cirrhosis and severe portal hypertension. Compensated patients with higher baseline HVPG had evidence of a small treatment effect. Emricasan treatment appeared safe and well-tolerated. LAY SUMMARY: Cirrhosis (scarring of the liver) is the main consequence of non-alcoholic steatohepatitis (NASH). Cirrhosis leads to high pressure in the portal vein which accounts for most of the complications of cirrhosis. Reducing portal pressure is beneficial in patients with cirrhosis. We studied the possibility that emricasan, a drug that improves inflammation and scarring in the liver, would reduce portal pressure in patients with NASH-related cirrhosis and severe portal hypertension. Our results in a large, prospective, double-blind study could not demonstrate a beneficial effect of emricasan in these patients. CLINICAL TRIAL NUMBER: Clinical Trials.gov #NCT02960204.

Selonsertib for patients with bridging fibrosis or compensated cirrhosis due to NASH: Results from randomized phase III STELLAR trials.

BACKGROUND & AIMS: Apoptosis signal-regulating kinase 1 (ASK1) plays a key role in hepatocyte injury, inflammation, and fibrosis in non-alcoholic steatohepatitis (NASH). We evaluated the safety and antifibrotic effect of selonsertib, a selective inhibitor of ASK1, in patients with advanced fibrosis due to NASH. METHODS: We conducted 2 randomized, double-blind, placebo-controlled, phase III trials of selonsertib in patients with NASH and bridging fibrosis (F3, STELLAR-3) or compensated cirrhosis (F4, STELLAR-4). Patients were randomized 2:2:1 to receive selonsertib 18 mg, selonsertib 6 mg, or placebo once daily for 48 weeks. Liver biopsies were performed at screening and week 48 and non-invasive tests of fibrosis (NITs) were evaluated. The primary efficacy endpoint was the proportion of patients with ≥1-stage improvement in fibrosis without worsening of NASH at week 48. Additional endpoints included changes in NITs, progression to cirrhosis (in STELLAR-3), and liver-related clinical events. RESULTS: Neither trial met the primary efficacy endpoint. In STELLAR-3, fibrosis improvement without worsening of NASH was observed in 10% (31/322, p = 0.49 vs. placebo), 12% (39/321, p = 0.93 vs. placebo), and 13% (21/159) of patients in the selonsertib 18 mg, selonsertib 6 mg, and placebo groups, respectively. In STELLAR-4, the primary endpoint was achieved in 14% (51/354; p = 0.56), 13% (45/351; p = 0.93), and 13% (22/172) of patients, respectively. Although selonsertib led to dose-dependent reductions in hepatic phospho-p38 expression indicative of pharmacodynamic activity, it had no significant effect on liver biochemistry, NITs, progression to cirrhosis, or adjudicated clinical events. The rates and types of adverse events were similar among selonsertib and placebo groups. CONCLUSIONS: Forty-eight weeks of selonsertib monotherapy had no antifibrotic effect in patients with bridging fibrosis or compensated cirrhosis due to NASH. LAY SUMMARY: Patients with non-alcoholic steatohepatitis (NASH) can develop scarring of the liver (fibrosis), including cirrhosis, which increases the risks of liver failure and liver cancer. We tested whether 48 weeks of treatment with selonsertib reduced fibrosis in patients with NASH and advanced liver scarring. We did not find that selonsertib reduced fibrosis in these patients. TRIAL REGISTRATION DETAILS: Clinicaltrials.gov numbers NCT03053050 and NCT03053063.

Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection.

BACKGROUND: Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct-acting antiviral agents (DAAs) have limited retreatment options. METHODS: We conducted two phase 3 trials involving patients who had been previously treated with a DAA-containing regimen. In POLARIS-1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks. Patients who were infected with HCV of other genotypes (114 patients) were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group. In POLARIS-4, patients with HCV genotype 1, 2, or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir-voxilaprevir (163 patients) or sofosbuvir-velpatasvir (151 patients) for 12 weeks. An additional 19 patients with HCV genotype 4 infection were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group. RESULTS: In the three active-treatment groups, 46% of the patients had compensated cirrhosis. In POLARIS-1, the rate of sustained virologic response was 96% with sofosbuvir-velpatasvir-voxilaprevir, as compared with 0% with placebo. In POLARIS-4, the rate of response was 98% with sofosbuvir-velpatasvir-voxilaprevir and 90% with sofosbuvir-velpatasvir. The most common adverse events were headache, fatigue, diarrhea, and nausea. In the active-treatment groups in both trials, the percentage of patients who discontinued treatment owing to adverse events was 1% or lower. CONCLUSIONS: Sofosbuvir-velpatasvir-voxilaprevir taken for 12 weeks provided high rates of sustained virologic response among patients across HCV genotypes in whom treatment with a DAA regimen had previously failed. (Funded by Gilead Sciences; POLARIS-1 and POLARIS-4 ClinicalTrials.gov numbers, NCT02607735 and NCT02639247 .).

Noninvasive Tests Accurately Identify Advanced Fibrosis due to NASH: Baseline Data From the STELLAR Trials.

Accurate noninvasive tests (NITs) are needed to replace liver biopsy for identifying advanced fibrosis caused by nonalcoholic steatohepatitis (NASH). We analyzed screening data from two phase 3 trials of selonsertib to assess the ability of NITs to discriminate advanced fibrosis. Centrally read biopsies from the STELLAR studies, which enrolled patients with bridging fibrosis and compensated cirrhosis, were staged according to the NASH Clinical Research Network classification. We explored associations between fibrosis stage and NITs, including the nonalcoholic fatty liver disease fibrosis score (NFS), fibrosis-4 (FIB-4) index, Enhanced Liver Fibrosis (ELF) test, and liver stiffness by vibration-controlled transient elastography (LS by VCTE). The performance of these tests to discriminate advanced fibrosis, either alone or in combinations, was evaluated using areas under the receiver operating characteristic curve (AUROCs) with 5-fold cross-validation repeated 100 times. Of the 4,404 patients screened for these trials, 3,202 had evaluable biopsy data: 940 with F0-F2 fibrosis and 2,262 with F3-F4 fibrosis. Significant differences between median values of NITs for patients with F0-F2 versus F3-F4 fibrosis were observed: -0.972 versus 0.318 for NFS, 1.18 versus 2.20 for FIB-4, 9.22 versus 10.39 for ELF, and 8.8 versus 16.5 kPa for LS by VCTE (all P < 0.001). AUROCs ranged from 0.75 to 0.80 to discriminate advanced fibrosis. FIB-4 followed by an LS by VCTE or ELF test in those with indeterminate values (FIB-4 between 1.3 and 2.67) maintained an acceptable performance while reducing the rate of indeterminate results. Conclusion: Among patients being considered for enrollment into clinical trials, NITs alone or in combination can reduce the need for liver biopsy to discriminate advanced fibrosis caused by NASH. The predictive value of these tests for general screening will require confirmation in a real-world population.

Ombitasvir/paritaprevir/ritonavir and dasabuvir with or without sofosbuvir for patients with hepatitis C virus genotype 1 infection who failed a prior course of direct-acting antiviral therapy.

INTRODUCTION: Despite high efficacy of current direct-acting antiviral agents (DAAs) in treating chronic hepatitis C virus (HCV) infection, a small portion of patients fail treatment. QUARTZ-I was a phase 2, open-label, multicenter, two-part study that assessed the safety and efficacy of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) with dasabuvir (DSV) with or without the addition of sofosbuvir (SOF) and/or ribavirin (RBV) in DAA treatment-experienced adults with chronic HCV GT1 infection. MATERIALS AND METHODS: Genotype 1 HCV-infected patients with or without compensated cirrhosis had prior treatment failure to any DAA (part 1) or ledipasvir/SOF (part 2). Patients received OBV/PTV/r + DSV ± SOF with or without RBV for 12 or 24 weeks. The primary endpoint of this study is the percentage of patients achieving sustained virologic response at post-treatment week 12 (SVR12). RESULTS: In part 1 of the study, 95.5% (21/22) of patients achieved SVR12, and in part 2, the SVR12 rate was 85.7% (6/7). Most adverse events (AEs) were mild and moderate in severity. Two serious AEs occurred and were assessed as not being related to study drug, of which one resulted in study drug discontinuation. Two patients experienced grade 3 elevations of serum alanine aminotransferase, and no other grade ≥3 laboratory abnormalities were observed. CONCLUSION: The multi-targeted regimen of OBV/PTV/r + DSV ± SOF with or without RBV was effective in the treatment of patients who failed previous DAA regimens including NS3/4A protease and NS5A and NS5B polymerase inhibitors. These results provide a promising outcome for patients that traditionally had limited treatment options.

Ribavirin dose management in HCV patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin.

BACKGROUND & AIMS: Some individuals with hepatitis C virus infection treated with direct-acting antivirals require ribavirin to maximize sustained virological response rates. We describe the clinical management of ribavirin dosing in hepatitis C virus-infected patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin. METHODS: We performed a post hoc analysis of patients receiving ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin for 12 or 24 weeks in six phase 3 trials. Multivariate stepwise logistic regression models assessed predictors associated with ribavirin dose adjustments and with developing anaemia. RESULTS: Of 1548 patients, 100 (6.5%) modified ribavirin dose due to haemoglobin declines, of which 99% achieved sustained virological response at 12 weeks post-treatment. Median time to first ribavirin dose reduction was 37 days. Low baseline haemoglobin was significantly associated with an increased risk of requiring ribavirin dose modification (odds ratio: 0.618 [0.518, 0.738]; P < .001) and developing anaemia (odds ratio: 0.379 [0.243, 0.593]; P < .001). CONCLUSIONS: Ribavirin dose reductions were infrequent, occurred early in treatment, and did not impact sustained virological response at 12 weeks post-treatment. Patients with low baseline haemoglobin should be monitored for on-treatment anaemia.

ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV.

BACKGROUND: The interferon-free regimen of ABT-450 with ritonavir (ABT-450/r), ombitasvir, and dasabuvir with or without ribavirin has shown efficacy in inducing a sustained virologic response in a phase 2 study involving patients with hepatitis C virus (HCV) genotype 1 infection. We conducted two phase 3 trials to examine the efficacy and safety of this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis. METHODS: We randomly assigned 419 patients with HCV genotype 1b infection (PEARL-III study) and 305 patients with genotype 1a infection (PEARL-IV study) to 12 weeks of ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin administered according to body weight or to matching placebo for ribavirin. The primary efficacy end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) 12 weeks after the end of treatment. RESULTS: The study regimen resulted in high rates of sustained virologic response among patients with HCV genotype 1b infection (99.5% with ribavirin and 99.0% without ribavirin) and among those with genotype 1a infection (97.0% and 90.2%, respectively). Of patients with genotype 1b infection, 1 had virologic failure, and 2 did not have data available at post-treatment week 12. Among patients with genotype 1a infection, the rate of virologic failure was higher in the ribavirin-free group than in the ribavirin group (7.8% vs. 2.0%). In both studies, decreases in the hemoglobin level were significantly more common in patients receiving ribavirin. Two patients (0.3%) discontinued the study drugs owing to adverse events. The most common adverse events were fatigue, headache, and nausea. CONCLUSIONS: Twelve weeks of treatment with ABT-450/r-ombitasvir and dasabuvir without ribavirin was associated with high rates of sustained virologic response among previously untreated patients with HCV genotype 1 infection. Rates of virologic failure were higher without ribavirin than with ribavirin among patients with genotype 1a infection but not among those with genotype 1b infection. (Funded by AbbVie; PEARL-III and PEARL-IV ClinicalTrials.gov numbers, NCT01767116 and NCT01833533.).

Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection.

BACKGROUND: Effective treatment for hepatitis C virus (HCV) genotype 1 infection in patients who have not had a sustained virologic response to prior interferon-based therapy represents an unmet medical need. METHODS: We conducted a phase 3, randomized, open-label study involving patients infected with HCV genotype 1 who had not had a sustained virologic response after treatment with peginterferon and ribavirin, with or without a protease inhibitor. Patients were randomly assigned to receive the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor sofosbuvir in a once-daily, fixed-dose combination tablet for 12 weeks, ledipasvir-sofosbuvir plus ribavirin for 12 weeks, ledipasvir-sofosbuvir for 24 weeks, or ledipasvir-sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Among the 440 patients who underwent randomization and were treated, 20% had cirrhosis and 79% had HCV genotype 1a infection. The rates of sustained virologic response were high in all treatment groups: 94% (95% confidence interval [CI], 87 to 97) in the group that received 12 weeks of ledipasvir-sofosbuvir; 96% (95% CI, 91 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir and ribavirin; 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 95 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir and ribavirin. No patient discontinued treatment owing to an adverse event. The most common adverse events were fatigue, headache, and nausea. CONCLUSIONS: Treatment with a once-daily, single-tablet regimen of ledipasvir and sofosbuvir resulted in high rates of sustained virologic response among patients with HCV genotype 1 infection who had not had a sustained virologic response to prior interferon-based treatment. (Funded by Gilead Sciences; ION-2 ClinicalTrials.gov number, NCT01768286.).

Efficacy of Sofosbuvir, Velpatasvir, and GS-9857 in Patients With Genotype 1 Hepatitis C Virus Infection in an Open-Label, Phase 2 Trial.

BACKGROUND & AIMS: The best regimen to re-treat patients who do not respond to direct-acting antivirals (DAAs) and the feasibility of further shortening regimens is unclear. We assessed the efficacy and safety of the combination of the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the NS3/4A protease inhibitor GS-9857 in patients with hepatitis C virus genotype 1 infection. METHODS: We performed an open-label trial at 32 sites in the United States and at 2 sites in New Zealand of 197 patients with genotype 1 hepatitis C virus infection, with or without compensated cirrhosis, who were treatment-naive or were treated previously with a DAA. Between March 2, 2015, and September 1, 2015, patients received sofosbuvir-velpatasvir (400 mg/100 mg in a fixed-dose combination) plus GS-9857 (100 mg) once daily for 6-12 weeks, plus ribavirin for 1 treatment group consisting of treatment-naive patients with cirrhosis. The primary end point was sustained virologic response 12 weeks after treatment (SVR12). RESULTS: Among treatment-naive patients without cirrhosis, 71% (24 of 34; 95% confidence interval [CI], 53-85) achieved SVR12 after 6 weeks of treatment and 100% (36 of 36; 95% CI, 90%-100%) achieved SVR12 after 8 weeks of treatment. Among treatment-naive patients with cirrhosis, 94% (31 of 33; 95% CI, 80-99) achieved SVR12 after 8 weeks of treatment and 81% (25 of 31; 95% CI, 63-93) achieved SVR12 after 8 weeks of treatment with ribavirin. Among DAA-experienced patients treated for 12 weeks, 100% without cirrhosis (31 of 31; 95% CI, 89-100) and 100% with cirrhosis (32 of 32; 95% CI, 89-100) achieved SVR12. The most common adverse events were headache, diarrhea, fatigue, and nausea. One patient (<1%) discontinued treatment because of adverse events. CONCLUSIONS: In a phase 2 open-label trial, we found 8 weeks of treatment with sofosbuvir-velpatasvir plus GS-9857 to be safe and effective in treatment-naive patients; 12 weeks was safe and effective in patients previously treated with DAAs. The combination was safe and effective in patients with or without compensated cirrhosis. Clinicaltrials.gov no: NCT02378935.